This Mentored Career Development Award (K01) will support Dr. Rodrigo A. Espana's long-term career objective of establishing an independent systems neuroscience program within an academic setting. Dr. Espana is interested in the actions of neuromodulators on arousal and motivated behaviors. In the proposed research program, Dr. Espana will utilize self-administration, microdialysis, and voltammetric techniques to examine the contribution of the excitatory neuropeptide hypocretin/orexin to reward and addiction processing. Cocaine addiction is a chronic relapsing disease characterized by repetitive, compulsive drug abuse despite negative physical, psychological, and social consequences. Despite huge advances in the neuroscience of drug abuse, available drugs for the treatment of cocaine addiction are ineffective or intolerable and consequently no approved pharmacotherapies currently exist. The hypocretins are relatively recently identified neuropeptides that participate in the regulation of arousal, locomotor activity, and a variety of motivated behaviors. Recently, emerging evidence indicates that the hypocretin system exerts a facilitatory influence on reward function and that these actions involve activation of dopamine neurons of the ventral tegmental area. Given the potential that the hypocretin system regulates reward associated with drug abuse, the proposed research program will employ a multidisciplinary approach to investigate hypocretin modulation of cocaine self-administration and the dopaminergic correlates that underlie these actions. To characterize the contribution of hypocretin systems in the regulation of arousal and motivated behaviors, particularly as it relates to drug abuse, this proposal will investigate: 1) The extent to which the hypocretin system influences cocaine-self administration; 2); Whether the hypocretin system participates in cocaine-induced dopamine release within the nucleus accumbens; and 3) To what degree the hypocretin systems regulates spontaneous dopamine spike activity within the nucleus accumbens. Completion of this work will provide information on the extent to which hypocretin participates in reward processing, the extent to which these actions involve the mesolimbic DA system, and will offer insight into the neural mechanisms underlying the addiction process. Further the results obtained from these studies may form the foundations to generate novel pharmacotherapies for drug abuse.